Metastasis is the multi-step process by which tumor cells disseminate from the primary tumor site and invade into surrounding tissues and organs. An early phase of metastasis in most solid tumors, including cutaneous melanoma, is the conversion of a neoplastic cell from a non-motile state to a motile state. This conversion requires the acquisition of multiple proficiencies that allow the cell to escape from the primary tumor mass, properly sense its microenvironment, and respond to cues found within that environment. Changes associated with this conversion include both morphological and genotypic (genetic and epigenetic) alterations. For many tumors, this conversion is associated with an epithelial-to-mesenchymal transition (EMT), which promotes the acquisition of a motile phenotype. Importantly, EMT is not unique to cancer cells, but is a process vital to the normal embryonic development of many tissues and organs. Specifically, pluripotent neural crest cells, which originate as epithelial cells in the dorsal neural tube, must undergo an EMT in order to delaminate and migrate from the neural tube to give rise to various derivatives, including melanocytes. Thus, not only are neural crest and melanoma cells related ancestrally (melanocytes are derivatives of the neural crest), metastatic melanoma cells and embryonic neural crest cells share many similar traits. Indeed, the processes of neural crest induction, delamination, and migration (including EMT) appear remarkably similar to the process of metastasis. However, the details surrounding these two invasion programs remain to be elucidated. Using novel in vivo imaging strategies, we have shown that human metastatic melanoma cells transplanted into the chick embryonic neural crest microenvironment invade into the host tissue and migrate along embryonic, ancestrally related neural crest cell migratory pathways. We hypothesize that the migration of melanoma cells simulates the early developmental processes of neural crest induction, delamination and migration. We postulate that the analysis of human melanoma cells transplanted into the chick neural crest embryonic microenvironment provides a novel and valid in vivo model system in which to study the initiation of melanoma metastasis. To test our hypothesis, we propose the following specific aims: 1) Compare/contrast the initial steps of melanoma metastasis with the delamination and invasion program of embryonic neural crest cells; 2) Identify properties that enable melanoma cells to recapitulate the neural crest invasion program in order to test the predisposition hypothesis in vivo. We expect that successful completion of these studies will advance our understanding of the metastatic process, specifically focusing on early tumor cell dissemination, leading to the identification of metastasis-specific biomarkers that will aid in the early and accurate diagnosis of cutaneous malignant melanoma.